This application claims priority under 35 U.S.C. xc2xa7xc2xa7119 and or 365 to FR-99/04745 filed in France on Apr. 15, 1999; the entire content of which is hereby incorporated by reference.
1. Technical Field of the Invention
The present invention relates to novel (poly)thiaalkynoic compounds and to pharmaceutical/cosmetic compositions comprised thereof; the subject compounds are especially useful in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds of structural formula (I) below in accordance with the present invention exhibit activity with respect to the transactivation of receptors of the PPAR type and more particularly of receptors of the PPAR-xcex1 subtype and find applications, in particular, for the treatment of inflammatory conditions such as rheumatoid arthritis, lupus and psoriasis.
The compounds according to the invention can also be formulated into cosmetic compositions for body and hair hygiene, in particular to regulate the metabolism of cutaneous lipids, to restore the skin barrier function, or to promote differentiation and to inhibit epidermal proliferation.
2. Description of the Prior Art
It is known to this art that a number of substances or active agents play an important role in the inflammatory process in the skin such as acne, dermatoses, such as for example psoriasis, eczema, and the like. These substances, among which are prostaglandins, hydroxyeicosatetraenoic acids, thromboxanes and leukotrienes, all have a common origin which is arachidonic acid (see, in particular, Voorhees, xe2x80x9cLeukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Other Dermathoses,xe2x80x9d Arch. Dermatol., Vol. 119, Jul. 1983, 541-547).
The formation of these substances results essentially from the conversion, after release, of the arachidonic acid bound by an ester bond to the lipids present in the epidermis (for example the phospholipids).
There have previously been recommended, for the treatment of skin diseases, either cyclooxygenase inhibitors which prevent the formation of prostaglandins, such as indomethacin, vitamin E, and the like; or substances capable of inhibiting lipoxygenases, such as eicosatetraynoic acid.
There have also been proposed, for the treatment of psoriasis, 5,8,11,14-eicosatetraynoic acid, as well as 5,8,11-eicosatriynoic acid and the lower alkyl esters thereof (compare, for example, U.S. Pat. No. 4,190,669), or the replacement of the methylene group at the 3-position in the structure of 5,8,11-eicosatriynoic acid or of 5,8,11,14-eicosatetraynoic acid with a heteroatom, such as sulfur or with a sulfoxide or sulfone group (see, EP-342,115).
It has now unexpectedly and surprisingly been determined that by shortening the length of the chain of unsaturated fatty acids of the thiaeicosa(poly)ynoic type, compounds were provided which are activators of PPAR-type receptors and, more particularly, activators which are selective for a subtype of PPAR-xcex1 receptors.
These acids present, in addition, the advantage of a cost which is much less than their longer-chain homologs.
It has also now been determined, surprisingly, that by replacing the methylene group at the 8-position in the unsaturated 3-thia fatty acid chain with a heteroatom such as sulfur, or with a sulfoxide or sulfone group, activators of PPAR-type receptors and, more particularly, activators which are selective for a subtype of PPAR-xcex1 receptors were also provided.
The present invention thus features such novel acids, as well as the derivatives thereof, such as the esters and amides.
The novel compounds according to the invention have the following structural formula (I):
R1xe2x80x94Yxe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94R2xe2x80x83xe2x80x83(I)
in which Y is (a) an xe2x80x94S(O)t radical, wherein t is an integer equal to 0, 1 or 2, (b) a xe2x80x94CH2xe2x80x94 radical, (c) a xe2x80x94Cxe2x89xa1Cxe2x80x94 radical, or (d) a xe2x80x94CHxe2x95x90CHxe2x80x94 radical; R1 is a linear or branched alkyl radical having from 1 to 18 carbon atoms which is optionally substituted with one or more halogen atoms, a linear or branched alkenyl radical having from 1 to 18 carbon atoms, or a linear or branched alkynyl radical having from 1 to 18 carbon atoms, with the proviso that such R1 radical may comprise one or more oxygen atoms and/or nitrogen atoms and/or sulfur atoms, with the further provisos, that when Y is (b), then R1 contains a number of atoms ranging from 1 to 12, inclusive, preferably from 4 to 12, inclusive, and even more preferably from 6 to 12, inclusive, that when Y is (c), then R1 contains a number of atoms ranging from 1 to 10, inclusive, preferably from 4 to 10, inclusive, and even more preferably from 6 to 10, inclusive, and that when Y is different from (b) and R1 is an unsaturated radical or comprises a heteroatom, then the unsaturation and/or the heteroatom of R1 cannot be at the xcex1 position with respect to Y; R2 is (a) a tetrazolyl radical of the formula: 
(b) a nitrile radical, (c) an oxazolinyl radical of the formula: 
(d) a xe2x80x94CH2OR3 radical, (e) a xe2x80x94COxe2x80x94R4 radical, wherein R3 and R4 are as defined below; R3 is a hydrogen atom, a lower alkyl radical, a monohydroxyalkyl radical having from 1 to 6 carbon atoms, or a polyhydroxyalkyl radical having from 2 to 6 carbon atoms, a cycloaliphatic radical having from 3 to 6 carbon atoms, or a tetrahydropyranyl radical; R4 is (a) a hydrogen atom, (b) a lower alkyl radical, (c) an xe2x80x94NRxe2x80x2 (Rxe2x80x3) radical, wherein Rxe2x80x2 and Rxe2x80x3 are as defined below, or (d) an xe2x80x94OR5 radical, wherein R5 is as defined below; R5 is (a) a hydrogen atom, (b) a linear or branched alkyl radical having from 1 to 18 carbon atoms, (c) a monohydroxyalkyl radical having from 1 to 6 carbon atoms, (d) a polyhydroxyalkyl radical having from 2 to 6 carbon atoms and comprising from 2 to 5 hydroxyl groups, (e) an aryl radical, (f) an aralkyl radical which is optionally substituted with one or more linear or branched alkyl radicals having from 1 to 18 carbon atoms, one or more xe2x80x94COxe2x80x94Rxe2x80x2xe2x80x3 radicals, or one or more xe2x80x94Oxe2x80x94Rxe2x80x2xe2x80x3 radicals, wherein Rxe2x80x2xe2x80x3 is as defined below; Rxe2x80x2 and Rxe2x80x3, which may be identical or different, are each a hydrogen atom, a lower alkyl radical, an alkenyl radical having from 3 to 4 carbon atoms, a cycloaliphatic radical having from 3 to 6 carbon atoms, an aryl or aralkyl radical which is optionally substituted, an amino acid or amino sugar residue, with the proviso that Rxe2x80x2 and Rxe2x80x3 may together form a heterocycle; and Rxe2x80x2xe2x80x3 is a hydrogen atom, or a linear or branched alkyl radical having from 1 to 18 carbon atoms.
This invention also relates to and features the salts of the compounds of formula (I) wherein R2 represents a carboxylic acid function, and the geometric and optical isomers of said compounds of formula (I).
When the compounds according to the invention are provided in the form of addition salts with a base, advantageously they are salts of an alkali or alkaline earth metal, or, alternatively, salts of zinc, magnesium or strontium, of an organic amine or the quaternary ammonium salts, when they contain at least one free acid function.
When the compounds of the invention are provided in the form of addition salts with an acid, they are pharmaceutically or cosmetically acceptable salts which are obtained by addition of an inorganic or organic acid, in particular hydrochloric, hydrobromic, sulfuric, acetic, citric, fumaric, hemisuccinic, maleic and mandelic acid.